Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

Faculty of Pharmacy Department of Pharmaceutical Chemistry University of Belgrade Belgrade Serbia

Faculty of Science Department of Chemistry University of Hradec Kralove Hradec Kralove Czech Republic

Medical Faculty of the Military Medical Academy University of Defence Belgrade Serbia

National Poison Control Centre Department of Experimental Toxicology and Pharmacology Military Medical Academy Belgrade Serbia

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